Colorectal cancer (CRC), the second leading cause of cancer death in the U.S., has long been recognized as a genetic disease. Advancement in microbial detection technology has revolutionized our view of many human diseases, and infectious etiologies have been suggested for CRC. Fusobacterium nucleatum (Fn), a gram-negative common oral anaerobe, has been shown to stimulate CRC via its unique FadA adhesin. The goal of the current proposal is to investigate the mechanisms by which Fn promotes CRC. FadA stimulates CRC cell growth by binding to E-cadherin and activating Wnt/-catenin signaling. Such stimulation is specific for colorectal carcinoma cells because FadA binding to other types of cells does not stimulate cell growth. We hypothesize that Fn stimulates CRC in conjunction with specific host genetic mutations. Since CRC initiates from cancer stem cells in the colon, we further hypothesize that Fn interacts with specific cancer-initiating stem cells to promote CRC. To test these hypotheses, we propose two specific aims: (i) To determine the host and bacterial components specific for Fn-stimulated colorectal tumorigenesis in vitro; and (ii) to investigate how Fn stimulates colorectal tumorigenesis in vivo. From this study, we anticipate gaining novel insights into the mechanism of colorectal tumorigenesis, and identify novel therapeutic targets for prevention and treatment of CRC. Thus, it implies significant translational potential.